This invention is in the field of clinical immunology and relates to compounds having immunosuppressive properties. Of particular interest is a family of phenylacetonitrilealkylaminoalkyl-o-substituted aryl compounds for reducing recipient rejection of transplanted organs, and for treatment of autoimmune or inflammatory diseases, allergic or asthmatic reactions and septic shock.
Successful organ transplantation requires effective physiological and pharmacological intervention of the immune system of an organ recipient. Immunologic mechanisms are universal among the human species. But histocompatibility variations between donor and recipient lead inevitably to rejection of donor tissue by stimulation of the recipient""s immune system except, perhaps, in donor-recipient pairing of the monozygotic type. One approach to intervention of immune response in an organ transplant recipient, especially a recipient targeted for an allogenic or homologous graft, is by the use of immunosuppressive drugs. These drugs have been used to prolong survival of transplanted organs in recipients in cases involving, for example, transplants of kidney, liver, heart, bone marrow and pancreas.
There are several types of immunosuppressive drugs available for use in reducing organ rejection in transplantation. Such drugs fall within three major classes, namely: antiproliferative agents, antiinflammatory-acting compounds and inhibitors of lymphocyte activation.
Examples of the class of antiproliferative agents are azathioprine, cyclophosphamide and methotrexate. The compound azathioprine acts by interrupting DNA synthesis through inhibition of purine metabolism. The compound cyclophosphamide is an alkylating agent which interferes with enzyme actions and nucleotide cross-linking. The compound methotrexate is a folic acid antagonist which interferes with nucleotide synthesis. While drugs of the antiproliferative class may be effective immunosuppressives in organ transplant recipients by limiting cell proliferation, these drugs which mediate mitosis and cell division have severe side effects on normal cell populations which have a high turn-over rate, such as bone marrow cells and cells of the gastrointestinal (GI) tract lining. Accordingly, such drugs often have severe side effects, particularly, bone marrow depression, liver damage, hair loss and GI tract disturbances.
A second class of immunosuppressive drugs for use in transplantation is provided by compounds having antiinflammatory action. Representatives of this drug class are generally known as adrenal corticosteroids and have the advantage of not exerting globally systemic cytotoxic effects. These compounds usually act by inhibiting T-cell proliferation, or by reducing IL-2 production, or by reducing chemotaxis, or by reducing neutrophil or macrophage activity. Typical examples of adrenal corticosteroids are prednisone and prednisolone. Compounds of this class are sometimes used in combination with cytotoxic agents, such as compounds of the antiproliferative class because the corticosteroids are significantly less toxic. But the adrenal corticosteroids lack specificity of effect and can exert a broad range of metabolic, antiinflammatory and auto-immune effects. Typical side effects of this class include increased organ-recipient infections and interference with wound healing, as well as disturbing hemodynamic balance, carbohydrate and bone metabolism and mineral regulation.
A third class of immunosuppressive drugs for use in organ transplantation is provided by compounds which generally prevent or inhibit lymphocyte activation. Such compounds usually act by blocking activated T-cell proliferation, or by inhibiting IL-2 production, or by inhibiting lymphokine production which depresses B-cell and macrophage actions. The cyclosporin family of compounds is the leading example of drugs in this class. Such compounds are fungal metabolites which have been found to be very effective in suppressing helper T cells so as to reduce both cellular and humoral responses to newly-encountered antigens. Cyclosporins alter macrophage and lymphocyte activity by reducing lymphokine secretion and, in particular, by interfering with activation of antigen-specific CD-4 cells, by preventing IL-2 secretion and secretion of many T-cell products, as well as by interfering with expression of receptors for these lymphokines. Cyclosporin A, in particular, has been used extensively as an immunosuppressor agent in organ transplantation. Other microbial metabolites include cyclosporins such as cyclosporin B and cyclosporin G, and another microbial product known as FK-506. Cyclosporin A suppresses humoral immunity as well as cell-mediated reactions. Cyclosporin A is indicated for organ rejection in kidney, liver, heart, pancreas, bone-marrow and heart-lung transplants. Cyclosporin A is also useful in the treatment of autoimmune and inflammatory diseases, including rheumatoid arthritis, Crohn""s disease, Graves ophthalmopathy, severe psoriasis, aplastic anemia, multiple-sclerosis, alopecia areata, penphigus and penphigoid, dermatomyositis, polymyositis, Behcet""s disease, uveitis, pulmonary sarcocidiosis, biliary cirrhosis, myasthenia gravis and atopic dermatitis.
Cyclosporins do possess several significant disadvantages. Firstly, while cyclosporins have provided significant benefits in organ transplantation, cyclosporins are non-specific immunosuppressives. Thus, immunologic reactions to transplanted tissue are not totally impeded, and desirable immune reactions may be reduced against other foreign antigens. Secondly, cyclosporins can produce severe side effects in many organ recipients. And cyclosporins show host-variable effects on the liver, the CNS and GI tract. Significant among the adverse side effects are damage to the kidney and hyperplasia of gum tissue.
Thus, the need remains for efficacious, selective immunosuppressive drugs in organ transplantation, especially for grafts between less-than-perfectly matched donor-recipient pairs.
Phenylacetonitrile compounds are known for use in treatment of cardiovascular diseases. For example, U.S. Pat. No. 3,261,859 describes phenylacetonitrile compounds, including the well-known compound verapamil, for use as coronary dilators. U.S. Pat. No. 4,593,042 describes certain bicycloamino-substituted phenylacetonitrilealkyl compounds, including several specific compounds having an isopropyl group attached to the alkylene alpha carbon of the phenylacetonitrile nucleus. Such compounds are characterized as calcium ion blockers for use in treatment of hypertension. U.S. Pat. No. 4,681,970 describes bicycloamino-substituted phenylacetonitrilealkyl compounds, several specific compounds of which have a long chain alkyl group (i.e., twelve carbons) attached to the alkylene alpha carbon of the phenylacetonitrile nucleus. These compounds are characterized as calcium channel blockers for treatment of hypertension.
Phenylacetonitrile compounds have been investigated for other pharmaceutical purposes. For example, certain calcium channel blocking agents, including verapamil, have been investigated for antiproliferative effects on T-cell mitogenesis [G. Walz et al, Transplantation, 47, 33-334 (1989)]. Various calcium channel blockers, including verapamil and nifedipine, have been studied for interaction with stimulated T-lymphocytes [A. Nell et al, Scan. J. Immunology, 24, 283-290 (1986)]. German Offen. 3826796 published Feb. 8, 1990 describes substituted phenylacetonitrile compounds for use in overcoming resistance to antimalarial or anticancer agents. The calcium antagonists verapamil, nifedipine and nicardipine were compared and found to produce dose-dependent acute and chronic antiinflammatory effects [W. R. Chen et al, Acta. Pharmacologica Sinica, 11(3), 281-285 (1990)].
Reduction in recipient rejection of a transplanted organ, or treatment of an autoimmune or inflammatory disease, or an allergic reaction or asthmatic condition, or treatment of septic shock may be accomplished by a method to suppress immune response in a recipient or treatment subject, which method comprises administering to the subject a therapeutically-effective amount of an immunosuppressive compound of Formula I: 
wherein m is one or two; wherein n is a number selected from one to ten, inclusive;
wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl, alkenyl, cycloalkenyl, aralkoxycarbonylalkyl, alkynyl, alkylthiocarbonylalkyl, alkylthiothiocarbonylalkyl, arylthiocarbonylalkyl, arylthiothiocarbonylalkyl, aralkylthiocarbonylalkyl, alkylarylthiocarbonylalkyl, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl;
wherein each of R2 and R3 is independently selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl and alkylthiocarbonylalkyl;
wherein each of R4, R5 and R7 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonylalkyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and wherein each of R2 through R5 and R7 through R16 may be further independently selected from radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonylalkyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, and radicals of the formula 
xe2x80x83wherein A is selected from divalent alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein each r is a number independently selected from zero to six, inclusive; wherein each of R17 through R29 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy,. alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonylalkyl, aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl and arylsulfonyl;
and wherein any of the foregoing A and R1 through R29 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxylalkyl, alkylthiocarbonylalkyl and alkylsulfonylalkyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
A preferred class consists of compounds within Formula I wherein m is one or two; wherein n is a number selected from one to nine, inclusive;
wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl, alkylaryloxycarbonylalkyl, alkenyl, cycloalkenyl, aralkoxycarbonylalkyl and alkynyl;
wherein each of R2 and R3 is independently selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, and mercaptoalkyl;
wherein each of R4, R5 and R7 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, mercapto, and wherein each of R2 through R5 and R7 through R16 may be further independently selected from radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl(alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, mercapto, and radicals of the formula 
xe2x80x83wherein A is selected from divalent alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein each r is a number independently selected from zero to five, inclusive; wherein each of R17 through R27 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio,
and wherein any of the foregoing A and R1 through R27 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cycloalkenyl, cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
A more preferred class consists of compounds within Formula I wherein m is one or two; wherein n is a number selected from one to eight, inclusive;
wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl,
wherein each of R2 and R3 is independently selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and alkoxycarbonylalkyl,;
wherein each of R4, R5 and R7 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkoxycarbonyloxy, and wherein each of R2 through R5 and R7 through R16 may be further independently selected from radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, and radicals of the formula 
xe2x80x83wherein A is selected from divalent alkyl, alkenyl and alkynyl groups; wherein X is oxygen atom or sulfur atom; wherein each r is a number independently selected from zero to four, inclusive; wherein each of R17 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptoalkyl, and alkoxycarbonyloxy;
and wherein any of the foregoing A and R1 through R24 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroylalkyl, cyanoamino, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl and carboxylalkyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
An even more preferred class consists of compounds within Formula I wherein m is one or two; wherein n is a number selected from one to seven, inclusive;
wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkoxycarbonylalkyl, alkenyl and alkynyl;
wherein each of R2 and R3 is independently selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxyalkyl and alkoxycarbonylalkyl;
wherein each of R4, R5 and R7 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, and wherein each of R2 through R5 and R7 through R16 may be further independently selected from radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, phenylalkyl, phenyl, benzoyl, phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl, alkylcarbonylalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, and radicals of the formula 
wherein A is selected from divalent alkyl, alkenyl and alkynyl groups; wherein each r is a number independently selected from zero to four, inclusive; wherein each of R17 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenylalkyl and phenyl;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, phenylalkyl, benzoyl, phenoxy, phenoxyalkyl, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, mercaptoalkyl and alkoxycarbonyloxy; and wherein any of the foregoing A and R1 through R24 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, phenylalkyl, hydroxyalkyl, cyano, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, phenyl, alkylcarbonylalkyl, alkoxycarbonylalkyl and carboxylalkyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
An even more highly preferred class consists of compounds within Formula I selected from compounds of Formula II: 
wherein m is one or two; wherein n is a number selected from one to six, inclusive; wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl;
wherein each of R8, R9, R10 and R12 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, phenoxy, benzyloxy, and radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, phenoxy, phenalkoxy, and radicals of the formula 
wherein A is a spacer group independently selected from one or more groups of the formula 
wherein each of R30 and R31 is independently selected from hydrido, alkyl, cycloalkyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy, phenoxy, alkoxyalkyl, benzyloxy, cyano, alkanoyl, 
wherein each of R36, R37, R38 and R39 is independently selected from hydrido, alkyl and phenyl; wherein R30 and R31 may be taken together to form oxo or exomethylene; wherein each of R32, R33, R34 and R35 is independently selected from hydrido, alkyl, hydroxyalkyl and alkoxyalkyl;
wherein each of R17, R18, R19, R20, R21, R22, R23 and R24 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl and phenalkyl;
wherein each r is a number independently selected from zero to four, inclusive;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and alkynyl;
and wherein any of the foregoing A and R1, R6, R8, R9, R10, R12 through R24 and R30 through R39 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, benzyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl and phenyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
A more highly preferred class consists of compounds within Formula I wherein m is one or two; wherein n is a number selected from one to five, inclusive;
wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl and alkynyl;
wherein each of R8, R9, R10 and R12 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals of the formula 
xe2x80x83with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, and radicals of the formula 
wherein A is a spacer group independently selected from one or more groups of the formula 
wherein each of R30 and R31 is independently selected from hydrido, alkyl, cycloalkyl, phenyl, benzyl, hydroxy, hydroxyalkyl, alkoxy and alkoxy and alkoxyalkyl;
wherein each of R32, R R34 and R35 is independently selected from hydrido, alkyl, hydroxyalkyl and alkoxyalkyl;
wherein each of R17, R18, R21 and R22 is independently selected from hydrido and alkyl;
wherein each r is a number independently selected from zero to four, inclusive;
wherein R6 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, benzyl, alkenyl and alkynyl;
and wherein any of the foregoing A and R1, R6, R8, R9, R10, R12 through R18, R21, R22 and R30 through R35 groups having a substitutable position may be substituted by one or more groups independently selected from alkyl, alkenyl, alkynyl, hydroxyalkyl and alkoxyalkyl;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
An even more highly preferred class consists of compounds within Formula II wherein m is one or two; wherein n is a number selected from one to five, inclusive; wherein R1 is selected from hydrido, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, alkenyl and alkynyl; wherein R6 is selected from loweralkyl; wherein each of R8, R9, R10 and R12 through R16 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and alkoxyalkyl; with the proviso that at least one of R12 and R16 must be selected from hydroxy, alkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylalkenyl, alkylaminocarbonyl and alkoxyalkyl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.
A family of compounds of specific interest within Formula I consists of the following compounds and pharmaceutically-acceptable salts thereof, as follows:
methyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
ethyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
n-propyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
n-butyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
n-hexyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-N-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-(1,1-dimethylethyl)-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylaminolethyl]ethyl]-N-(1,1-dimethylethyl)-N-pentylxe2x80x944,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-ethyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-methyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-propyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylaminolethyl]ethyl]-N-butyl-4,5-dimethoxybenzamide;
2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-N-pentyl-4,5-dimethoxybenzamide;
xcex1-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-methylphenyl)ethyl]methylamino]propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-ethylphenyl)ethyl]methylamino]propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-propylphenyl)ethyl]methylamino]propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-butylphenyl)ethyl]methylamino]propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-(4,5-dimethoxy-2-pentylphenyl)ethyl]methylamino]propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butenyl) phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-pentenyl) phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1[3-[[2-[4,5-dimethoxy-2-(3-oxo-1E-butanyl) phenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile;
xcex1-[3-[[2-[2-(hydroxymethyl)-4,5-dimethoxyphenyl]ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl) benzeneacetonitrile; and
1-methylethyl 2-[2-[[4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl]methylamino]ethyl]-4,5-dimethoxybenzoate.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to a oxygen atom to form a hydroxyl group; or, as another example, two hydrido groups may be attached to a carbon atom to form a xe2x80x94CH2xe2x80x94 group. Where the term xe2x80x9calkylxe2x80x9d is used, either alone or within other terms such as xe2x80x9chydroxyalkylxe2x80x9d, the term xe2x80x9calkylxe2x80x9d embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about fifteen carbon atoms. For some substituents, more preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d, that is, radicals having one to about ten carbon atoms. For some substituents, most preferred alkyl radicals are lower alkyl radicals having one to about five carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The terms xe2x80x9calkylolxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term xe2x80x9calkenylxe2x80x9d embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety. The term xe2x80x9calkynylxe2x80x9d embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term xe2x80x9ccycloalkenylxe2x80x9d embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term xe2x80x9calkoxyalkylxe2x80x9d also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl and biphenyl. The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms xe2x80x9cbenzylxe2x80x9d and xe2x80x9cphenylmethylxe2x80x9d are interchangeable. The terms xe2x80x9caryloxyxe2x80x9d and xe2x80x9carylthioxe2x80x9d denote, respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms xe2x80x9csulfinylxe2x80x9d and xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO2. The term xe2x80x9caralkoxyxe2x80x9d, alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term xe2x80x9cacylxe2x80x9d whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. xe2x80x9cLower alkanoylxe2x80x9d is an example of a more preferred sub-class of acyl. The term xe2x80x9camidoxe2x80x9d denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. The amido radical can be attached to the nucleus of a compound of the invention through the carbonyl moiety or through the nitrogen atom of the amido radical. The term xe2x80x9calkenylalkylxe2x80x9d denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term xe2x80x9cheteroarylxe2x80x9d embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment.
Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl and n-hexadecyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.
It is preferred that certain selections of radicals for R1 be avoided. Radicals for R1 which should preferably be avoided are alkyl, alkenyl and alkynyl moieties having a hydroxy, alkoxy or double or triple bond attached to the alpha carbon of the moiety, that is, the carbon attached to the nitrogen atom of Formula I on which R1 is substituted. It is also preferred that certain selections of radicals for R6 be avoided. Radicals for R4 which should preferably be avoided are sulfhydryl, amino and mono- and di-substituted amino.
Also included in the family of compounds of Formulas I are isomeric forms including diastereoisomers, regioisomers and the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases, including quaternary ammonium salts. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formulas I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, xcex2-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
Compounds of general Formula I can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of Formula I with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.
Compounds embraced by Formula I may be prepared in accordance with Scheme I, which follows, wherein each of the R substituents are as defined in Formula I above, except where further noted.
Synthesis of the compounds of Formula I can be achieved by the reaction of bis-electrophile, sequentially, with two nucleophiles (Scheme I). The bis-electrophile can be, for example, an alkyl chain, substituted at the desired positions with a halogen or a sulfonic acid ester or the like or by a group that can be transformed into such an electrophile. It may be convenient, upon treatment with a nucleophile, that the two electrophilic groups have a differential reactivity toward nucleophilic substitution, e.g., a chloro group and a bromo group. Examples of bis-electrophiles are 3-bromo-chloropropane, 4-bromo-chlorobutane, 4-bromobutane-1-para-toluenesulfonate, 5-chloro-1-methyl-butane trifluoromethanesulfonate and the like. Examples of nucleophiles that can be reacted with the above bis-electrophiles are the anions of aryl-propionitriles, prepared using non-nucleophilic bases, and primary or secondary amines. Non-nucleophilic bases are, for example, sodium hydride, potassium hydride, lithium di-iso-propyl amide (LDA, the salt of a sterically hindered amine) and the like. Electrophilic groups are indicated in Scheme I by E1 and E2. 
The following Examples 1-9 are detailed descriptions of the methods of preparation of compounds of Formula I. These detailed preparations fall within the scope of, and serve to exemplify, the above described Generic Procedures which form part of the invention. These Examples 1-9 are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight unless otherwise indicated.